Oxylipins, aging and Alzheimer’s disease

阿尔茨海默病(AD)约占全部痴呆病例的三分之二，而AD病例的数量 预计到2050年将增加两倍。找到一条调节AD的新途径不仅会改善我们的 了解神经退化背后的机制，也将显著提高生活质量 老年人口的比例。最近的人体研究显示，omega-3水平和 Omega-6膳食脂肪与大脑老化。然而，这些效应背后的具体途径(S)仍然存在 很大程度上是未知的。这项提案的总体目标是阐明omega-3和omega-6的作用 多不饱和脂肪酸(PUFAs)在AD中的代谢产物。Omega-3和omega-6多不饱和脂肪酸的代谢产生 数以百计的脂质信号分子通过花生四烯酸(AA)级联被称为氧脂素。这些氧磷脂 在炎症、血压调节、血管生成和纤维化中发挥动态平衡作用，以及它们在体内的作用 水平受疾病进展的影响很大。此外，最近的研究表明，特定的 氧化脂质可能在AD发病中起重要作用。Aβ和tau的沉积是阿尔茨海默病的特征，衰老仍然存在 阿尔茨海默病的关键危险因素之一。因此，在这个提议中，我们假设Aβ和Tau的沉积以及 衰老调节体内的氧脂水平，从而影响动物的神经元健康。 为了检验我们的假设，我们将开发一种多学科的方法，通过收集有机和 分析化学家、神经生物学家、AD研究人员和模型生物体的使用。我们将1)建立 细胞色素P450多不饱和脂肪酸代谢产物内源性水平与A-β、tau-与衰老的关系 诱导神经退行性变；2)确定特异性氧脂对β、tau和衰老诱导的作用(S) 神经退行性变。我们将以秀丽隐杆线虫(C.elegans)为模式生物，研究其对人体健康的影响。 Aβ和tau，以及衰老对多不饱和脂肪酸代谢的影响，因为容易产生大量的年龄同步 人口，以及可用于开展这项研究的现有遗传工具的数量。此外，许多 在线虫和人类之间，衰老和神经退化途径以及氧脂途径是保守的。 我们将使用最先进的超高效液相色谱与串联质谱仪相结合的方法来 测定线虫在整个生物体和转基因菌株中的氧脂水平 过度表达Aβ和tau。我们将测试受β和AFP沉积显著影响的氧脂的效果 使用过表达A、β和tau的转基因菌株进行神经退行性检测中的tau和衰老。在成功之后 在这个项目中，我们可以确定一条对衰老和神经退行性变研究重要的新途径。我们的结果 也可以解释omega-3和omega-6多不饱和脂肪酸对衰老的影响(S)。

Alzheimer’s disease (AD) comprises about two-thirds of the total dementia cases, and the number of AD cases is expected to triple by 2050. Identifying a new pathway that modulates AD will not only improve our understanding of the mechanism behind neurodegeneration, but will also significantly improve the quality of life of the aged population. Recent human studies revealed a causal relationship between the levels of omega-3 and omega-6 dietary lipids and aging of the brain. However, the specific pathway(s) behind such effects remains largely unknown. The overall goal of this proposal is to elucidate the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) metabolites in AD. Metabolism of omega-3 and omega-6 PUFAs generates hundreds of lipid-signaling molecules called oxylipins through the arachidonic acid (AA) cascade. These oxylipins play a homeostatic role in inflammation, blood pressure regulation, angiogenesis, and fibrosis, and their in vivo levels are significantly affected by disease progression. Furthermore, recent studies suggested that specific oxylipins may play an important role in AD. The deposition of Aβ and tau are hallmarks of AD, and aging remains one of the key risk factors of AD. Therefore, in this proposal, we hypothesize that deposition of Aβ and tau and aging modulate the in vivo oxylipin levels, which affects the neuronal health of animals. To test our hypothesis, we will develop a multidisciplinary approach by assembling expertise from organic and analytical chemists, neurobiologists, AD researchers and the use of a model organism. We will 1) establish the relationship between endogenous levels of CYP450 PUFA metabolites and the effect of Aβ-, tau-and aging- induced neurodegeneration and; 2) determine the effect(s) of specific oxylipins on Aβ-, tau-and aging induced neurodegeneration. We will use Caenorhabditis elegans (C. elegans) as a model organism to study the effect of Aβ and tau, and aging on PUFA metabolism because of the ease of generating large age-synchronized populations, and the number of established genetic tools available to carry out this research. Furthermore, many aging and neurodegenerative pathways and oxylipin pathways are conserved between C. elegans and humans. We will use state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry to determine oxylipins levels in C. elegans over the lifespan of the organism and in transgenic strains that overexpress Aβ and tau. We will test the effect of oxylipins that are significantly affected by deposition of Aβ and tau and aging in neurodegenerative assays using transgenic strains that overexpress Aβ and tau. Upon success of this project, we could identify a new pathway important for aging and neurodegeneration research. Our results could also explain the effect(s) of omega-3 and omega-6 PUFAs on aging.